The neurohumoral systems and kidneys are intimately linked in the control of cardiovascular dynamics. Previous experimental and theoretical studies suggest that abnormalities of kidney function, manifest by impaired pressure natriuresis, underlie all forms of hypertension studied thus far. In some cases, these disturbances originate intrarenally, but they also occur via activation of neurohumoral mechanisms that impair renal excretory capability. Therefore, a large share of our research has been directed toward understanding the intrarenal and neurohumoral mechanisms that regulate kidney function, and how they are altered in pathophysiologic conditions such as hypertension. During the previous project period, we studied extensively obesity hypertension, which has special relevance to human essential hypertension. Our studies indicated that activation of the sympathetic nervous system (SNS), via the renal nerves, and intrarenal structural changes play a major role in the pathophysiology of obesity hypertension. The proposed studies will determine quantitative importance and mechanisms by which humoral systems activate the SNS and the role of neurohumoral and hemodynamic mechanisms in mediating biochemical, structural, and functional changes that occur in the kidneys in the early phases of obesity. We will utilize a model of dietary-induced obesity, produced by feeding a high fat diet in chronically instrumented dogs, that closely mimics the neurohumoral, renal, and cardiovascular changes observed in obese humans. The major goals of this proposal are: 1) to test the hypothesis that systemic or CNS actions of leptin, angiotensin II (AngII), insulin, and non-esterified fatty acids (NEFA), acting individually or synergistically, increase renal sympathetic activity, impair renal excretory, function, and raise arterial pressure in obesity; 2) to test the hypothesis that increased arterial pressure, increased sympathetic activity, AngII, and insulin interact to stimulate renal medullary matrix formation, glomerular injury, and other structural and biochemical changes in the kidneys in the early phases of obesity hypertension. The proposed work will utilize an integrative approach, employing chronically instrumented dogs as well as biochemical, molecular biological, histological, and morphometric methods, to elucidate the role of neurohumoral mechanisms in the pathophysiology of obesity hypertension.